The present invention relates to a sustained release pharmaceutical preparation in tablet form, where the active ingredient is an anti-convulsant medication, preferably carbamazepine.
Seizures caused by epilepsy require long-term therapy and most anti-epileptic medications must be administered several times a day.sup.1. Carbamazepine is used as an anti-convulsant medication in the treatment of epilepsy. Although carbamazepine (CMZ) has an initial half-life of 20-40 hrs, the half life becomes shorter through autoinduction during repetitive administration. Carbamazepine's half-life is decreased to 12 hrs with a single dose and 8 hrs upon multiple dose.sup.2. Therefore, sustained release formulations of these drugs have been developed. Carbamazepine is reported to be quite erratic in its absorption.sup.3. Possible reasons for irregular or inconsistent absorption are (a) low water solubility and physico-chemical properties of the molecule leading to very slow dissolution rate in the gastrointestinal fluid, (b) anticholinergic properties of the drug which may become more evident during prolonged treatment and thus modify its gastrointestinal transit time. Plasma t.sub.max is reported to be 4-8 hrs after oral administration, but may be delayed for more than 24 hrs. Plasma protein binding is about 75% and plasma levels of carbamazepine are variable ranging from 0.5 to 25 mcg/ml. Usual adult therapeutic levels are between 4-12 mcg/ml. The predominant pathway of metabolism involves conversion to carbamazepine 10,11-epoxide. This metabolite is as active pharmacologically as the parent compound and its concentration in plasma and brain may reach 50% of that of carbamazepine. The 10,11-epoxide further metabolizes to inactive compound, which is excreted in the urine.
A sustained release formulation, such as is provided by the present invention would smooth the fluctuations in plasma drug concentrations and diminish concentration related side effects of the drug, which is sometimes close to a daily dosage of up to 2000 mg.
German Patent No. 4423078 discloses a delayed-release oral dosage form of carbamazepine. The formulation disclosed differs significantly from the present invention. German Patent No. 4423078 discloses a tablet, containing water soluble plasticizers and a coating which contains talc. The formulation of the present invention is a disintegrating tablet, containing hydrophobic plasticizers and carbamazepine particles coated by a coating dispersion of a different quantitative composition and not containing talc.
Japanese Patent Application No. 94-298499 discloses a controlled release formulation of carbamazepine. However, the formulation disclosed is substantially different from the present invention. The formulation of the Japanese patent contains 3 coating layers, compared to the single coating layer of the present invention.
None of these prior art references suggested or disclosed the use of the combination of coating dispersion, hydrophobic plasticizer and disintegrating agent of the carbamazepine formulation of the present invention.
It would be highly advantageous to have, an effective sustained release carbamazepine formulation drug which is lower in cost and yet which is suitable for the treatment of seizures caused by epilepsy, as is described in the present invention.